Device for transdermal administration for the treatment of urinary tract disorders

ABSTRACT

This invention provides a device containing a compound of formula (I), wherein R represents a saturated or unsaturated C 2-7  aliphatic acyl group optionally substituted by one or more halogen atoms, a hydroxy group, a C 1-6  alkoxy group, a carboxyl group, a C 2-7  alkoxycarbonyl group, a 5 to 7-membered cycloalkyl group, a phenyl or naphthyl group; a C 2-6  hydroxyalkyl group; an aliphatic acyloxyalkyl group having a C 2-7  acyl group and a C 1-6  alkyl group; a C 1-6  alkyl group substituted by a C 1-6  alkoxy group, a carboxyl group, a C 2-7  alkoxycarbonyl group, a C 2-7  alkoxycarbonyl group substituted by a phenyl or naphthyl group, a carbamoyl group, a mono- or di-(C 1-6  alkyl)-substituted carbamoyl group or a cyano group; a benzoyl or naphthoyl group optionally substituted by one or more halogen atoms; a furoyl group or a pyridylcarbonyl group; and R 1  represents a C 1-6  alkyl group optionally substituted by one or more halogen atoms, a phenyl or a naphthyl group; the carbon atom marked “*” represents a carbon atom in (R)-configuration, (S)-configuration or a mixture thereof. The TTS is efficient in the treatment of urinary tract disorders, such as benign prostatic hypertrophy.

FIELD OF THE INVENTION

The present invention relates to devices for the transdermal delivery ofindoline compounds of formula (I) for treating or preventing urinarytract disorders. Moreover, the invention relates to the use of indolinecompounds of formula (I) for the preparation of a medicament fortransdermal application.

TECHNICAL BACKGROUND

The active ingredient of the device according to the present inventionis an indoline compound of formula (I)

wherein

R represents a saturated or unsaturated C₂₋₇ aliphatic acyl groupoptionally substituted with one or more halogen atoms, a hydroxy group,a C₁₋₆ alkoxy group, a carboxyl group, a C₂₋₇ alkoxycarbonyl group, a 5to 7-membered cycloalkyl group, a phenyl or naphthyl group; a C₂₋₆hydroxyalkyl group; an aliphatic acyloxyalkyl group having a C₂₋₇ acylgroup and a C₁₋₆ alkyl group; a C₁₋₆ alkyl group substituted with a C₁₋₆alkoxy group, a carboxyl group, a C₂₋₇ alkoxycarbonyl group, a C₂₋₇alkoxycarbonyl group substituted with a phenyl or naphthyl group, acarbamoyl group, a mono- or di-(C₁₋₆ alkyl)-substituted carbamoyl groupor a cyano group; a benzoyl or naphthoyl group optionally substitutedwith one or more halogen atoms; a furoyl group or a pyridylcarbonylgroup; and

R¹ represents a C₁₋₆ alkyl group optionally substituted with one or morehalogen atoms, a phenyl or a naphthyl group;

the carbon atom marked “*” represents a carbon atom in(R)-configuration, (S)-configuration or a mixture thereof.

A particularly preferred compound of formula (I) is(-)-(R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]indoline-7-carboxamide(KMD 3213) which has the structure as shown below:

The compounds of formula (I) as well as methods for their preparationare disclosed in EP A 600 675. The compounds are said to be useful forthe treatment of dysuria. KMD 3213 is disclosed in EP A 600 675 as aparticularly preferred embodiment of the compounds of formula (I).

The indoline compounds of formula (I) are α-adrenoceptor antagonists.α-Adrenoceptor antagonist are generally thought to be useful in treatingand preventing urinary tract disorders, such as dysuria, benignprostatic hypertrophy (BPH) or prostatic cancer (EP A 799 618 and EP A799 619).

Furthermore, it is known that KMD 3213 is an α-adrenoceptor subtypespecific antagonist, binding specifically to the α_(1a)-receptor (S.Murata, T. Taniguchi, I. Muramatsu, British Journal of Pharmacology(1999) 127, 19-26).

Urinary outlet obstruction in patients with BPH is attributed to amechanical component which is the urethral impression produced by thehypertrophy prostatic tissue, and a dynamic component related to thetone of urethral and prostatic smooth muscles. Stimulation ofα_(1a)-adrenoceptors of urethral and prostatic smooth muscles has beenshown to cause bladder outlet obstructions in patients suffering fromBPH.

Consequently, KMD 3213 was tested in animal models for its usefulness inthe treatment of urinary outlet obstructions in patients with BPH (K.Akiyama, M. Hora, S. Tatemichi, N. Masuda, S. Nakamura, R. Yamagishi, M.Kitazawa, J. Pharmacol. Exp. Thera. (1999) 241, 81-91).

Moreover, it has been postulated that α-adrenoceptor antagonists arecapable of preventing and treating urinary tract disorders such as BPHand prostate cancer causally (EP 799 618 and EP 799 619).

The indoline compounds of formula (I) have presently only been suggestedfor oral or parenteral administration. Other application forms of thesecompounds were not suggested previously.

In order to provide a reliable treatment for BPH the indoline compoundsof formula (I), and particularly KMD 3213, have to be administered in away that secures

-   -   (a) a sufficient bio-availability,    -   (b) a constant plasma level or at least a tight control of the        plasma level in view of the low therapeutic index, and    -   (c) provides for high patient compliance.

The desired combination of (a), (b) and (c) was previously impossible toachieve as all previously used administration forms of the indolinecompounds of formula (I), and in particularly KMD 3213 proved to showcertain disadvantages.

Firstly, the bio-availability of those compounds of formula (I) whenadministered orally is very low (about 20%), and the half-life ofcompounds such as KMD 3213 is short, i.e. in the range of 4.5 to 10hours.

Moreover, the relatively low therapeutic index of α-adrenoceptorantagonists such as the indoline compounds of formula (I) requires aconstant plasma level without periodic concentration peaks as obtainedby oral administration.

On the other hand, parenteral administration may often be undesirablefor the patient in view of the higher effort and stress (e.g. fear ofinjections) and the higher risk involved. Furthermore, intramuscular orsubcutaneous injection may cause local irritation of the skin or theunderlying tissue. Finally, it is difficult to provide the necessaryconstant and effective plasma level even by parenteral administrationunless constant infusions are applied.

The indoline compounds of formula (I) are relatively large compoundshaving a molecular mass of about 500 Da or more. KMD 3213 for examplehas a molecular mass of 495.5 Da. A person skilled in the art generallyconsiders a molecular mass of as high as about 500 Da as being in arange where transdermal application is no longer possible, i.e.compounds having a molecular mass of about 400 Da or more are normallynot suitable for transdermal administration.

Reference is made to Pfister (Pfister W. R. “Transdermal and DermalTherapeutic Systems: Current Status” in the standard textbook of Ghosh,T. K., Pfister, W. R., Yum S. I. (eds) “Transdermal and Topical DrugDelivery Systems”, Chapter 2, Interpharm Press, Buffalo Grove, Ill.1997, pp 33-112). On page 48 thereof it is stated: “In general thedesirable physicochemical, biopharmaceutical and pharmacokineticattributes of a candidate for passive TDD include the following: . . .Low molecular weight, (i.e. less than 400 daltons) . . . ”

Moreover, it is widely accepted that the MW has a large influence on thedrug absorption, e.g Potts and Guy have proposed the following equationfor predicting the skin permeability of drugs:log Kp (cm/sec)=−6.3 +0.71 log K _(oct)−0.0061 MW(Potts, R. O. and Guy, R. H. (1992) “Predicting skin permeability”.Pharmaceutical Research 9, 663-669). According to this equation, theskin permeability constant Kp has an exponential relationship to themolecular weight (MW) of a given substance.

An even stronger dependence of drug diffusion through the stratumcorneum on the molecular weight permeation of a drug has been determinedby Anderson & Raykar (J. Invest. Dermatol 93 (1989) 280) who found thatthe permeability coefficient of a solute across the stratum corneum isinversely proportional to the 4.6th power of its molecular weight.

In view of the above, it has been very surprising that by using a devicecontaining indoline compounds of formula (I) with a molecular size ofabout 500 Da, such as KMD 3213, the active agent can be administered ata steady state flux rate of about 3 mg per day across human skin for anextended period of time, e.g. for at least 24 hours, preferably for 72hours, resulting in uniform plasma levels of the active agent.

The flux rate obtained and the corresponding plasma level are sufficientto allow for a reasonable expectation that an effective prevention ortreatment of urinary tract disorders such as BPH or prostatic cancerwith less side effects can be provided.

It is to be understood that the term “treatment” in the context of thisinvention is meant to designate causal treatment or alleviation of thesymptoms of urinary tract disorders.

SUMMARY OF THE INVENTION

The present invention provides a device for transdermal administrationof a compound of formula (I) in order to achieve an effect in treatingor preventing urinary tract disorders, such as prostatic hypertrophy(BPH), in a mammal including human. Moreover, the invention concerns theuse of said compounds of formula (I) for the preparation of a medicamentfor transdermal administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Skin permeation profile across human skin for the patchformulation of the invention

DESCRIPTION OF THE INVENTION

The present invention provides a device for transdermal administrationof a compound of formula (I)

wherein

R represents a saturated or unsaturated C₂₋₇ aliphatic acyl groupoptionally substituted with one or more halogen atoms, a hydroxy group,a C₁₋₆ alkoxy group, a carboxyl group, a C₂₋₇ alkoxycarbonyl group, a 5to 7-membered cycloalkyl group, a phenyl or naphthyl group; a C₂₋₆hydroxyalkyl group; an aliphatic acyloxyalkyl group having a C₂₋₇ acylgroup and a C₁₋₆ alkyl group; a C₁₋₆ alkyl group substituted with a C₁₋₆alkoxy group, a carboxyl group, a C₂₋₇ alkoxycarbonyl group, a C₂₋₇alkoxycarbonyl group substituted with a phenyl or naphthyl group, acarbamoyl group, a mono- or di-(C₁₋₆ alkyl)-substituted carbamoyl groupor cyano groups; a benzoyl or naphthoyl group optionally substitutedwith one or more halogen atoms; a furoyl group or a pyridylcarbonylgroup; and

R¹ represents a C₁₋₆ alkyl group optionally substituted with one or morehalogen atoms, a phenyl or a naphthyl group;

the carbon atom marked “*” represents a carbon atom in(R)-configuration, (S)-configuration or a mixture thereof.

The device of the present invention is particularly useful in treatingor preventing urinary tract disorders, such as benign prostatichypertrophy (BPH) in mammals.

The term “mammals” as used herein is to be understood to mean mammaliananimals including humans.

In one embodiment of the invention the device for transdermaladministration may comprise a racemic mixture of compounds of formula I.

In another, more preferred embodiment of the present invention thedevice for transdermal administration comprises a compound of formula(I) which is essentially in its R-isomeric form or in its S-isomericform.

The term “essentially” as used in the present invention is intended tomean at least 95%, preferably at least 97%, more preferably at least 98%and even more preferable at least 99%. In other words, a compound thatis essentially in its R-isomeric form is in an amount of at least 95% inits R-isomeric form and in an amount of less than 5% in thecorresponding S-isomeric form.

In a preferred embodiment of the invention, the device for transdermaladministration comprises a compound of formula (I) which is(-)-(R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]amino]propyl]-indoline-7-carboxamide(KMD 3213).

For achieving an effect in treating or preventing urinary tractdisorders the compounds of formula (I) preferably have to beadministered through mammalian skin in a steady state flux rate of atleast 0.5 mg per day. More preferred are steady state flux rates of atleast 1 mg/day, even more preferred are flux rates of 1-5 mg/day andespecially preferred are flux rates of 2-4 mg/day.

As shown in Examples 1 and 2 (see further below) with the devicesprovided by the present invention, steady state flux rates of KMD 3213through human skin of 2.9 mg/day and through mouse skin of 2.7 mg/daycould be achieved.

As shown in FIG. 1 the steady state flux rate is achieved after a lagtime and is maintained for an extended period of time, i.e. for at least24 hours, preferably for 72 hours after the administration of the deviceto the patients skin. Once the typical lag phase after the initialadministration of the patch has been overcome, a continuous plasma levelis thus achievable.

A preferred embodiment of the present invention is therefore a devicefor the transdermal administration characterized in that it allows forthe administration of a compound of formula (I) through human and/oranimal skin in a steady state flux rate of at least 0.5 mg/day, morepreferred at least 1 mg/day, even more preferred 1-5 mg/day and inparticular preferred 2-4 mg/day.

The device of the present invention may be applied to the patient's skinfor at least 24 hours, preferably for 48 or 72 hours or even 7 days.

In order to achieve the desired flux rate it is important to have asufficient concentration of dissolved drug incorporated in the device.In a preferred embodiment of the present invention the device comprisesat least one layer wherein the drug is dissolved in a concentration ofat least 1% (w/w), for example 1-25% (w/w), preferably about 1 to 10%(w/w), most preferably 3-7% (w/w) and particularly preferred 4-6% (w/w).

Said device of the present invention comprises transdermal therapeuticsystems (TTS), such as patches or systems wherein the release of thecompounds is controlled by electric or osmotic means, e.g. iontophoreticor osmotic devices which are known to the skilled artisan.

In a preferred embodiment the device of the present invention is apatch.

In general, there are two types of designs for patches: a “reservoir”type and a “matrix” type.

In the reservoir type the drug, which is typically in the form of afluid, is contained within a walled reservoir whose basal surface ispermeable to the drug. The reservoir type of TTS may contain severaladditional layers such as a backing layer, a semi-permeable membranewhich controls the drug release rate, an adhesive layer and a removableprotective film.

In the matrix type the drug is dispersed in a polymer layer.

The systems of the matrix type in their simplest version comprise a onephase (monolayer) matrix. They consist of a backing layer, a selfadhesive matrix containing the active agent and a protective film whichis removed prior to use.

More complicated versions comprise multi-layer matrices, wherein thedrug may be contained in one or more non-adhesive polymer layers.

The TTS according to the present invention is preferably a matrixsystem. More preferably it is a one phase (monolayer) matrix system.

Usually the adhesive will be a pressure sensitive adhesive (PSA) or amixture of such adhesives and will form a matrix in which the activeingredient and the other components of the TTS are incorporated.

Moreover, the adhesive should preferably be pharmaceutically acceptablein a sense that it is biocompatible, non-sensitising and non-irritatingto the skin. Particularly advantageous adhesives for use in the presentinvention should further meet the following requirements:

-   1. Retained adhesive and co-adhesive properties in the presence of    moisture or perspiration, under normal temperature variations,-   2. Good compatibility with the compounds of formula (I), such as KMD    3213, as well as with the further excipients used in the    formulation.-   3. Providing sufficient solubility of the compounds of formula (I),    such as-KMD 3213, especially of the free base form of said    compounds.

Although different types of pressure sensitive adhesives may be used inthe present invention, it is preferred to use adhesives showingdissolution parameters which are similar to those of the compounds offormula (I). Such a preferred pressure sensitive adhesive for use in thedevice of the present invention can be an adhesive of the polyacrylatetype.

Polyacrylates are produced by radical polymerization of (meth)acrylicacid derivatives, wherein other suitable compounds, such as for examplevinyl acetate may be used as further monomers. It is to be understoodthat as used herein the term “polyacrylate” comprises polymerscomprising units derived from acrylic acid and/or methacrylic acid aswell as copolymers and mixtures thereof.

By selection of suitable monomers, the resulting adhesives may bedesigned in order to have specific properties, i.e. a favourabledissolving capacity for the active agent, a desired moveability of theactive agent in the matrix as well as a desired transfer rate via theskin. The transfer rate is essentially determined by the distributioncoefficient and the resorption of the active agent by the skin.

The pressure sensitive adhesive of the polyacrylate type may be ahomopolymer and/or copolymer of at least one acrylic and/or methacrylicacid derivative in the form of a solution in an organic solvent(solution type). The polyacrylate type adhesive may be in acrosslinkable or non-crosslinkable form. The crosslinking agent linksthe polymer chains via reactive groups. This may result in increasedcohesion of the adhesive.

Advantageously, the polymer adhesive of the polyacrylate type containsat least one of the following monomers:

Acrylic acid, acrylamide, hexyl acrylate, 2-ethyl-hexyl acrylate,hydroxy ethyl acrylate, octyl acrylate, butyl acrylate, methyl acrylate,glycidyl acrylate, methyl acrylate, methacrylic acid, methacrylamide,hexyl methacrylate, 2-ethyl-hexylamide acrylate, octyl methacrylate,methyl methacrylate, glycidyl methacrylate, vinyl acetate,vinylpyrrolidone, allyl acrylate.

More preferably the polymer adhesives of the acrylate type arecross-linkable adhesives polymerized from a combination of the followingmonomers:

-   2-ethyl-hexyl acrylate/n-butyl acrylate/butyl acrylate/acrylic acid,-   2-ethyl-hexyl acrylate/n-butyl acrylate/vinyl acetate/acrylic acid,-   2-ethyl-hexylacrylate/vinyl acetate/acrylic acid,-   2-ethyl-hexyl acrylate/vinyl acetate/allyl acrylate,-   2-ethyl-hexyl acrylate/vinyl acetate/divinyl benzene/acrylic acid,-   2-ethyl-hexyl acrylate/vinyl acetate/allyl methacrylate/acrylic    acid,-   2-ethyl-hexyl acrylate/vinyl acetate/2-hydroxy-ethyl acrylate,-   2-ethyl-hexyl acrylate/vinyl acetate/2-hydroxy-ethyl methacrylate,-   2-ethyl-hexyl acrylate/fumaric acid diethyl ester/acrylic acid,-   2-ethyl-hexyl acrylate/maleic acid diethyl ester/2-hydroxy-ethyl    acrylate.

As the preferred crosslinking agents the following compounds may bementioned: diphenyl-methan-4-diisocyanate, hexamethylene diisocyanate,isophoron diisocyanate, titanium acetylacetonate, aluminiumacetylacetonate, iron acetylacetonate, zinc acetylacetonate, magnesiumacetylacetonate, zirconium acetylacetonate,2-ethyl-1,3-hexanediol-titanate, tetra-iso-octyl-titanate,tetra-nonyl-titanate, polyfunctional propylene imine derivatives, etherderivatives of melamine formaldehyde resins, highly methylated urethaneresins, imino melamine resins.

The non-crosslinkable adhesives of the solution type may advantageouslybe polymerized from a combination of the following monomers:

-   2-ethyl-hexyl acrylate/n-butyl acrylate/vinyl acetate,-   2-ethyl-hexyl acrylate/vinyl acetate,-   2-ethyl-hexyl acrylate/n-butyl acrylate/vinyl acetate/allyl    acrylate,-   2-ethyl-hexyl acrylate/n n-butyl acrylate/allyl methacrylate,-   2-ethyl-hexyl acrylate/n-butyl acrylate/vinyl acetate/divinyl    benzene,-   2-ethyl-hexyl acrylate/fumaric acid diethyl ester/allyl acrylate,-   2-ethyl-hexyl acrylate/maleic acid diethyl ester/allyl acrylate,-   2-ethyl-hexyl acrylate/n-butyl acrylate/acrylamide/vinyl    acetate/allyl acrylate,-   2-ethyl-hexyl acrylate/n-butyl acrylate/iso-butyl acrylate/vinyl    acetate/allyl acrylate.

Moreover, some adhesives may be used in the form of aqueous dispersions(dispersion type). The use of these dispersion type adhesives mayinvolve the further advantage that during coating and drying noflammable or toxic solvents evaporate. Dispersion type adhesives mayadvantageously be polymerized from a combination of the followingmonomers:

-   n-butyl acrylate/iso-butyl acrylate/acrylic acid-   2-ethyl-hexyl acrylate/n-butyl acrylate/acrylic acid,-   2-ethyl-hexyl acrylate/n-butyl acrylate/2-hydroxy-ethyl acrylamide,-   2-ethyl-hexyl acrylate/n-butyl acrylate/vinyl acetate/acrylamide,-   2-ethyl-hexyl acrylate/n-butyl acrylate/vinyl    acetate/2-hydroxy-ethyl acrylate,-   2-ethyl-hexyl acrylate/n-butyl acrylate/allyl acrylate/acrylic acid,-   2-ethyl-hexyl acrylate/n-butyl acrylate/vinyl acetate/divinyl    benzene.

Suitable polyacrylates for use in the present invention are cross-linkedusing multivalent metal ions, in order to improve the physicalproperties of the adhesive or to adapt it to the specific requirements.The metal ions are normally employed in the form of metal chelates whichare soluble in organic solvents. Particularly suitable crosslinkingagents are aluminium acetyl acetonate and titanium acetyl acetonate.

If the adhesive used according to the present invention is apolyacrylate adhesive, the solvent capacity is generally dependent onthe type and amount of free functional groups in the adhesive.

Most preferred adhesives for use in the device of the present inventionare polyacrylates with polar groups, especially with free hydroxy-and/or carboxyl groups. Examples of such adhesives are polyacrylateswherein polar monomers such as e.g. hydroxy-ethyl acrylate,hydroxy-ethyl methacrylate, acrylic acid or methacrylic acid in anamount of about 1-10% (w/w), more preferred in an amount of 3-8% (w/w),most preferred in an amount of 4-6% (w/w) are used. Those adhesives arecommercially available under the tradename Duro-Tak® (National Starch &Chemicals; Hamburg).

Even more preferred for use in the device of the present invention areadhesives of the polyacrylate type wherein hydroxy-ethyl acrylate and/orhydroxy-ethyl methacrylate monomers are incorporated duringpolymerization in an amount of 3-8% (w/w), most preferred in an amountof 4-6% (w/w).

Such an adhesive may be obtained in line with the general proceduredescribed in U.S. Pat. No. 5,498,418 as follows: The adhesive can beobtained by radical polymerisation in a first stage of a mixtureconsisting of 21 to 40% by weight vinyl acetate, 55 to 70% by weight ofan acrylic acid-C₂₋₈-alkyl ester, and 3 to 10% by weight of an acrylicacid-C₂₋₄-hydroxyl acryl ester, with 100% by weight monomers in themixture, in an organic solvent, whereafter in a second stage aconventional crosslinking agent in an organic solvent and the activeingredient in the quantity required for the intended use of thetransdermal device (plaster) is admixed, if necessary in an organicsolvent, and finally in a third stage the resulting mixture of theparticular acrylate-vinyl acetate copolymer is crosslinked in anadditional stage, accompanied by heating and the removal of the organicsolvent or mixture of solvents used; the resulting active ingredient is“built into” the adhesive substance in a special manner by thesubsequent and additional crosslinkage of the special acrylate-vinylacetate copolymer. The acrylate-vinyl acetate copolymer has a relativeviscosity of 3.0 to 4.2 at 20° C.

Preferably the mixture of monomers contains 2-ethylhexylacrylate andhydroxyethylacrylate in addition to vinyl acetate. Preferably thesubsequent crosslinkage of the special acrylate-vinyl acetate copolymeris performed with a titanium acid ester consisting of polybutyl titanateand/or titanium acetylacetonate, more particularly in a quantity of 0.3to 3% by weight thereof, the percentages by weight being related to theweight of the copolymer.

A process for producing a TTS according to the invention may alsoinclude the steps of applying a solution of a copolymer, containing theactive ingredient in the required amount for the intended use of the TTSand a conventional crosslinker or mixture thereof, and obtained by theradical polymerisation of a mixture of monomers consisting of 21 to 40%by weight vinyl acetate, 55 to 70% by weight of an acrylicacid-C₂₋₈-alkyl ester and 1 to 10% by weight of an acrylicacid-C₂₋₄-hydroxyalkylester, in the required layer thickness to theprotective film of the TTS, and removing the solvent or mixture ofsolvents by heating, thus effecting an additional crosslinking of thespecial acrylate-vinyl acetate copolymer.

One embodiment of such a process is characterized in that theacrylate-vinyl acetate copolymer, the active ingredient and thecrosslinking agent are initially dissolved in a solvent which contains20 to 40% by weight of ethanol or an ethanol-methanol mixture, with asolids proportion consisting of 40 to 60% by weight of the mixture ofthe special acrylate-vinyl acetate copolymer, crosslinking agent and theactive ingredient.

A particular working example for the preparation of such aacrylate-vinyl acetate adhesive is disclosed in U.S. Pat. No. 5,498,418,col. 2, line 61 to col. 3, line 10, hereby incorporated by reference.

An especially preferred adhesive for use in the present invention is thecommercially available adhesive DuroTak® 387-2287 (National Starch &Chemicals; Hamburg).

For the preparation of the TTS according to the invention, a compound offormula (I), such as KMD 3213, is solved or suspended in ethanol oranother suitable organic solvent and subsequently the adhesive is addedwhile stirring.

If the adhesive contains a suitable solvent system, the active agent maybe directly added to the adhesive solution. Further auxiliary agents maybe added either to the adhesive solution, the solution of the activeagent or the adhesive solution containing the active agent.

In one particular preferred embodiment of the present invention thedevice of the present invention is a one phase matrix, wherein one ormore compounds of formula (I) are dissolved in a pressure sensitiveadhesive of the acrylate type in an amount of 1-10% (w/w), preferably3-7% (w/w), and most preferred 4-6% (w/w), and wherein said acrylatepreferably contains free polar groups, such as hydroxy groups or carboxygroups, as described further above. If a 7-day patch is desired, higherdrug concentrations will generally be required.

The thickness of the adhesive layer may be between 0.01 and 0.30 mm,preferably between 0.02 and 0.20 mm and most preferably between 0.03 and0.10 mm.

In a further preferred embodiment, the device further includes asolubilizer.

A solubilizer is an additive that inhibits the crystallisation of theactive agent during storage of the device. Examples of solubilizersknown in the art are, e.g. phthalic acid esters, adipic acid ester,monoglycerides, diglycerides, triglycerides, fatty acids and esters andderivatives thereof, higher alcohols and their derivatives, derivativesof nonylphenol or octylphenol, derivatives of sorbitol or mannitol,non-ionogenic tensides, polyoxyethylene alkyl ethers, derivatives ofricinus oil, sitosterin or polyvinylpyrrolidone.

Preferred solubilizers for use in the device of the present inventionare solubilizers which are capable of keeping the compounds of formula(I) in solution if said device is stored for a prolonged period of time.

It is presently considered that preferred solubilizers for inhibitingthe precipitation of the compounds of formula (I) are additives having apKa of about 4.5 to 6.0, more preferred 4.5 to 5.5, even more preferredbetween 4.8 and 5.1 and particularly preferred about 5.0 such as e.g.carboxylic acids, including particularly fatty acids.

In a preferred embodiment the devices of the present invention thuscontain a solubilizer, wherein said solubilizers are carboxylic acids.Most preferred solubilizers are fatty acids having a PKa of 4.8 to 5.1and at least 10 carbon atoms and which may or may not have one or moredouble bonds.

In an even more preferred embodiment of the present invention thesolubilizer may be chosen from the group comprising lauric acid,linoleic acid, stearic acid, palmitic acid and oleic acid.

A particularly preferred solubilizer for use in the device of thepresent invention is oleic acid.

The solubilizer is preferably present in an amount of about 50 to 500mol %, more preferred in an amount of 100 to 400 mol %, even morepreferred in an amount of 100 to 300 mol % and particularly preferred inan amount of about 200 mol % based on the active compound.

If for example KMD 3213 is used as the active ingredient, then oleicacid is preferably used in an amount of approximately 50 to 500 mol %,i.e. in an amount of 28 to 280% (w/w) based on the amount of KMD 3213.

The device of the present invention may therefore contain oleic acid ina concentration of about 0.28% to 28% (w/w) in a layer containing 1 to10% (w/w) KMD 3213. Typically, KMD 3230 may be present in aconcentration of 5% (w/w) in the adhesive layer, which may also containabout 5 to 6% (w/w) oleic acid.

The device of the present invention may further comprise a penetrationenhancer. Penetration enhancers are additives which enhance thepenetration of the active agent through mammalian skin. Examples ofpenetration enhancers are well known to the skilled artisan and comprisecitrate; fatty acids; fatty acid esters; glycerol and esters thereofsuch as e.g. glycerol monolaurate (GML); alcohols with up to 8carboxylic atoms, such as ethanol, 1,2-propandiol, dexpanthenol orpolyethyleneglycol; mixtures of alcohol and water; vitamin E andderivatives thereof; copolymers of ethylene and vinyl acetate;polyvinylpyrrolidone; copolymers of polyvinylpyrrolidone and vinylacetate; polypropyleneglycol.

Although the addition of a penetration enhancer may be possibly usefulin some embodiments of the invention, it is usually not necessary. Asshown in Example (I), flux rates of 2.7 to 2.9 mg KMD 3213 per day wereachieved using a one phase matrix type TTS.

In a preferred embodiment the device of the present invention istherefore devoid of any additive that enhances the penetration of thecompounds of formula (I) through mammalian skin.

In other embodiments of the invention the device may comprise additionaladditives such as stabilizers or swellable agents which are well knownto the skilled artisan.

In a preferred embodiment of the present invention, the device has abasal surface area of 5 to 50 cm², particularly of 10 to 20 cm². It goeswithout saying that a device having a surface area of, say, 20 cm² ispharmacologically equivalent to and may be exchanged by two 10 cm²devices or four 5 cm² devices having the same drug content per cm².Thus, the surface areas as indicated herein should be understood torefer to the total surface of all devices simultaneously administered toa patient.

Providing and applying one or several devices according to the inventionhas the pharmacological advantage over oral therapy that the attendingphysician can titrate the optimum dose for the individual patientrelatively quickly and accurately, e.g. by simply increasing the numberor size of devices given to the patient. Thus, the optimum individualdosage can often be determined after a time period of only about 3 weekswith low side effects.

A preferred content of a compound of formula I, such as KMD 3213 in thedevices according to the invention is in the range of 0.1 to 2.0 mg/cm².Still more preferred are 0.20 to 1.0 mg/cm². If a 7 day patch isdesired, higher drug contents will generally be required.

The device used in the present invention is preferably a patch having acontinuous adhesive matrix in at least its center portion containing thedrug. However, transdermal equivalents to such patches are likewisecomprised by the present invention, e.g. an embodiment where the drug isin an inert but non-adhesive matrix in the center portion of the deviceand is surrounded by an adhesive portion along the edges.

The device of the present invention may further comprise a backing film,which is a film being impermeable to the active compounds. Such a filmmay consist of polyester, polyamide, polyethylene, polypropylene,polyurethane, polyvinylchloride or of combinations of the aforementionedmaterials which may or may not be coated with an aluminium film or withaluminium vapour. The thickness of the backing film may be between 10and 100 μm, preferably between 20 and 40 μm.

The device of the present invention may further contain a release linerfoil, which will be removed immediately prior before the device will bebrought into contact with the mammalian skin. The release liner foil mayconsist of polyester, polyethylene or polypropylene which may or may notbe coated with aluminium film or aluminium vapour or fluoropolymers.Typically, the thickness of such a release liner ranges between 20 and300 μm and preferably between 50 and 100 μm.

The device according to the present invention is prepared by amanufacturing process comprising preparing a drug loaded adhesive,coating, drying or cooling and lamination to get the bulk product,converting the laminate into patch units via cutting and packaging.

In a further aspect, this invention relates to the use of a compound offormula (I), for example KMD 3213, for preparing a medicament fortransdermal administration.

Such a medicament may comprise the devices described above as well asointments, creams, sprays, gels or films, and the like, provided that asteady state flux rate of at least 0.5 mg per day through the mammalianskin is achieved. Even more preferred are steady state flux rates of atleast 1 mg/day, e.g. 1 to 5 mg/day or 2 to 4 mg/day.

In a preferred embodiment a compound of formula (I) is used forpreparing a medicament, wherein the medicament is a patch of the matrixtype, and most preferably a patch of the one phase matrix type.

In a particular preferred embodiment a compound of formula (I) is usedfor preparing a medicament, which is a one phase matrix type patch,wherein said compound is dissolved in the adhesive layer and wherein theadhesive is a of the polyacrylate type including polar groups.

Said medicament is particularly useful in treating and preventingurinary tract disorders, such as benign prostate hypertrophy andprostatic cancer and/or symptoms associated with these conditions.

In a still further aspect, this invention relates to a method oftreating urinary tract disorders, such as benign prostatic hypertrophy(BPH), by applying on a patient in need thereof the device containing acompound of formula (I) as described above.

The invention and the best mode for carrying it out will be explained inmore detail in the following non-limiting examples.

EXAMPLE 1

A TTS using a polyacrylate based pressure sensitive adhesive wasprepared as follows.

1 g of(-)-(R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]indoline-7-carboxamide(KMD 3213) was solved in 8 g ethanol, 1 g of oleic acid and 32.1 g of asolution containing 18 g of DuroTak® 387-2287 (in ethylacetate) wereadded while stirring. The resulting mixture was stirred (350 u/min)approximately one hour until a homogenous dispersion was obtained.

The dispersion was coated onto a polyester release liner (SCOTCHPAK®1022) with a suitable doctor knife and the solvents were removed in adrying oven at a temperature of 50° C. for about 30 minutes to obtain anadhesive matrix of 76 g/m² coating weight, which contained 5% (w/w)drug. The dried matrix film was laminated with a polyester type backingfoil (SCOTCHPAK® 1109). The individual patches were punched out of thecomplete laminate to a desired patch size (for example 5 cm², 10 cm², 20cm², 30 cm²) and sealed into pouches under the flow of nitrogen. Theobtained patches were studied using several test methods.

EXAMPLE 2

A TTS using a polyacrylate based pressure sensitive adhesive wasprepared as follows.

1 g of KMD 3213 was solved in 8 g ethanol, 1.2 g of oleic acid and 31.8g of a solution containing 17.8 g of DuroTak® 387-2287 (in ethylacetate)were added while stirring. The resulting mixture was stirred (350 u/min)approximately one hour until a homogenous dispersion was obtained.

The dispersion was coated onto a polyester release liner (SCOTCHPAK®1022) with a suitable doctor knife and the solvents were removed in adrying oven at a temperature of 50° C. for about 30 minutes to obtain anadhesive matrix of 81 g/m² coating weight, which contained 5% (w/w)drug. The dried matrix film was laminated with a polyester type tackingfoil (SCOTCHPAK® 1109). The individual patches were punched out of thecomplete laminate to a desired patch size (for example 5 cm², 10 cm², 20cm², 30 cm²) and sealed into pouches under the flow of nitrogen. Theobtained patches were studied using several test methods.

EXAMPLE 3

0.75 g of KMD 3213 was solved in 4 g ethanol, 0.5 g of Kollidon 90F and15.6 g of a solution containing 8.75 g DuroTak® 387-2287 (inethylacetate) were added while stirring. The resulting mixture wasstirred (700 u/min) approximately one hour until a homogenous dispersionwas obtained.

The dispersion was coated onto a polyester release liner (SCOTCHPAK®1022) with a suitable doctor knife and the solvents were removed in adrying oven at a temperature of 50° C. for about 30 minutes to obtain anadhesive matrix of 90 g/m² coating weight, which contained 7.5% (w/w)drug. The dried matrix film was laminated with a polyester type tackingfoil (SCOTCHPAK® 1109). The individual patches were punched out of thecomplete laminate to a desired patch size (for example 5 cm², 10 cm², 20cm², 30 cm²) and sealed into pouches under the flow of nitrogen. Theobtained patches were studied using several test methods.

EXAMPLE 4

0.5 g of KMD 3213 was solved in 4 g ethanol, 0.5 g of isopropylmyristateand 16.1 g of a solution containing 9 g DuroTak® 387-2287 (inethylacetate) were added while stirring. The resulting mixture wasstirred (700 u/min) approximately one hour until a homogenous dispersionwas obtained.

The dispersion was coated onto a polyester release liner (SCOTCHPAK®1022) with a suitable doctor knife and the solvents were removed in adrying oven at a temperature of 50° C. for about 30 minutes to obtain anadhesive matrix of 55 g/m² coating weight, which contained 5% (w/w)drug. The dried matrix film was laminated with a polyester type tackingfoil (SCOTCHPAK® 1109). The individual patches were punched out of thecomplete laminate to a desired patch size (for example 5 cm², 10 cm², 20cm², 30 cm²) and sealed into pouches under the flow of nitrogen. Theobtained patches were studied using several test methods.

Drug Release in Vitro (Flux Across Dialysis Membrane):

The assay was performed according to Tanojo et al. (journal ofControlled Release 45 (1997), 41-47).

In this test, the patch showed a high release rate per area unit. Due toa fast depletion of the reservoir the drug release rate was timedependent as expected.

Skin Permeation:

The skin permeation of KMD 3213 was also evaluated on hairless mouseskin and human skin. Human skin penetration assays were performed asdescribed by Tanojo et al. in Journal of Controlled Release 45 (1997),41-47. The concentration of KMD 3213 was measured by HPLC with a SymetryShield RP-8, 3.9*150 mm 5 μm column; T=35° C.; eluent:water/acetonitrile/trifluoracetic acid 800/200/1 (v/v/v); dectetion UVat 225 nm; flux rate 1.5 ml/min; injection volume: 100 μl at 23° C.

The flux measurements on hairless mouse skin were conducted using a TTSarea of 2.55 cm² fixed on mouse abdominal and back skin in a horizontaldiffusion cell. Immediately thereafter the acceptor chamber of the cellwas filled with phosphate buffer solution (0.066 molar) previouslyadjusted to 32±0.5° C. and pH 6.2, in an air-bubble free state, and therelease medium thermostatted to 32±0.5° C. At the time of sampling(after 3, 6, 24 and 48 hours) the release medium is exchanged with freshmedium thermostatted at 32±0.5° C. KMD 3213 was measured with HPLC asexplained above.

On hairless mouse skin a steady state skin permeation rate ofapproximately 2.7 mg/20 cm² per day was observed. On human skin thesteady state flux rate was equivalent to 2.9 mg/20 cm² per day.

The cumulative permeation rate on human skin of the device producedaccording to example 1 is shown in FIG. 1.

The permeation rates on human or mouse skin of the devices producedaccording to examples 1 to 4 are shown in table 1. TABLE 1 Cumulativepenetration of KMD 3213 (μg/5 cm²) through human skin (Examples 1 and 2)and through mouse skin (Examples 3 and 4) 6 hours 24 hours 48 hours 72hours Example 1 5.1 20.1 206.1 832.35 Example 2 1.8 23.25 335.25 1030.8Example 3 97.3 735.5 1152.1 n.d. Example 4 81 599.2 1000.8 n.d.n.d. = not determinedStability:

Stability tests of the devices produced according to Examples 1 and 2revealed that nucleation or crystal growth could not be observed duringa storage at 40° C. and 75% relative humidity for at least 3 months.

1. A device for transdermal administration, containing a compound of the formula (I)

wherein R represents a saturated or unsaturated C₂₋₇ aliphatic acyl group optionally substituted with one or more halogen atoms, a hydroxy group, a C₁₋₆ alkoxy group, a carboxyl group, a C₂₋₇ alkoxycarbonyl group, a 5 to 7-membered cycloalkyl group, a phenyl or naphthyl group; a C₂₋₆ hydroxyalkyl group; an aliphatic acyloxyalkyl group having a C₂₋₇ acyl group and a C₁₋₆ alkyl group; a C₁₋₆ alkyl group substituted with a C₁₋₆ alkoxy group, a carboxyl group, a C₂₋₇ alkoxycarbonyl group, a C₂₋₇ alkoxycarbonyl group substituted with a phenyl or naphthyl group, a carbamoyl group, a mono- or di-(C₁₋₆ alkyl)-substituted carbamoyl group or a cyano group; a benzoyl or naphthoyl group optionally substituted with one or more halogen atoms; a furoyl group or a pyridylcarbonyl group; and R¹ represents a C₁₋₆ alkyl group optionally substituted with one or more halogen atoms, a phenyl or a naphthyl group; the carbon atom marked “*” represents a carbon atom in (R)-configuration, (S)-configuration or a mixture thereof.
 2. The device for transdermal administration according to claim 1, characterized in that said compound of formula (I) essentially is in its R-isomeric form, S-isomeric form or in its racemic form.
 3. The device for transdermal administration according to any one of the preceding claims, characterized in that said compound of formula (I) is (-)-(R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]amino]propyl]-indoline-7-carboxamide (KMD 3213).
 4. The device according to any one of the preceding claims, characterized in that it administers a compound of formula (I) through mammalian skin in a steady state flux rate of at least 0.5 mg per day.
 5. The device for transdermal administration according to any one of the preceding claims, characterized by having a loading of a compound represented by formula (I) from about 0.1-2 mg/cm².
 6. The device according to any one of the preceding claims, characterized in that it comprises at least one layer wherein a compound of formula (I) is dissolved in a concentration of at least 1% (w/w).
 7. The device according to claim 6, wherein the compound of formula (I) is dissolved in a concentration between 3% and 7% (w/w).
 8. The device according to any one of the preceding claims, characterized in that it is a patch of the reservoir or the matrix type.
 9. The device according to any one of the preceding claims, characterized in that it is a patch of the matrix type, wherein said compound of formula (I) is dissolved in the adhesive.
 10. The device according to any one of the preceding claims, characterized in that it contains an adhesive of the polyacrylate type.
 11. The device according to any one of the preceding claims, characterized in that it further comprises a solubilizer.
 12. The device according to claim 13, wherein the solubilizer is a carboxylic acid.
 13. The device according to claims 13 or 14, wherein the solubilizer is oleic acid.
 14. The device according to any one of claims 11 to 13, wherein the solubilizer is present in an amount of 50 to 500 mol % based on the amount of the compound of formula (I) that is incorporated in the device.
 15. The device according to any of the preceding claims, wherein the device has a basal area of 5 to 50 cm².
 16. The device according to any one of the preceding claims, characterized in that it the compound represented by formula (I) for a predefined period of time, preferably for 48 or 72 hours, or up to 7 days.
 17. The use of a compound of formula (I)

wherein R represents a saturated or unsaturated C₂₋₇ aliphatic acyl group optionally substituted with one or more halogen atoms, a hydroxy group, a C₁₋₆ alkoxy group, a carboxyl group, a C₂₋₇ alkoxycarbonyl group, a 5 to 7-membered cycloalkyl group, a phenyl or naphthyl group; a C₂₋₆ hydroxyalkyl group; an aliphatic acyloxyalkyl group having a C₂₋₇ acyl group and a C₁₋₆ alkyl group; a C₁₋₆ alkyl group substituted with a C₁₋₆ alkoxy group, a carboxyl group, a C₂₋₇ alkoxycarbonyl group, a C₂₋₇ alkoxycarbonyl group substituted with a phenyl or naphthyl group, a carbamoyl group, a mono- or di-(C₁₋₆ alkyl)-substituted carbamoyl group or a cyano group; a benzoyl or naphthoyl group optionally substituted with one or more halogen atoms; a furoyl group or a pyridylcarbonyl group; and R¹ represents a C₁₋₆ alkyl group optionally substituted with one or more halogen atoms, a phenyl or a naphthyl group; the carbon atom marked “*” represents a carbon atom in (R)-configuration, (S)-configuration or a mixture thereof for the preparation of a medicament for transdermal application.
 18. The use according to claim 17, characterized in that said compound of formula (I) essentially is in its R-isomeric form, its S-isomeric form or its racemic form.
 19. The use according to claim 17, wherein the compound of formula (I) is (-)-(R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]amino]propyl]-indoline-7-carboxamide (KMD 3213).
 20. The use according to any one of claims 17-19, wherein said compound of formula (I) is administered through mammalian skin in a steady state flux rate of at least 0.5 mg/day.
 21. The use according to any one of claims 17-20, wherein the medicament for transdermal application is the device for transdermal administration according to any one of claims 1-16.
 22. The use according to any one of claims 17-20, wherein the medicament for transdermal application is an ointment, cream, spray, gel or film.
 23. The use according to any one of claims 17-22, wherein the medicament is for treating or preventing a urinary tract disorder and/or symptoms associated with this condition.
 24. The use according to claim 23, wherein the urinary tract disorder is benign prostatic hypertrophy.
 25. A method for treating or preventing a urinary tract disorder and/or symptoms associated with this condition in mammals, including human, by transdermally applying on the patient suffering from this disease a compound of formula (I)

wherein R represents a saturated or unsaturated C₂₋₇ aliphatic acyl group optionally substituted with one or more halogen atoms, a hydroxy group, a C₁₋₆ alkoxy group, a carboxyl group, a C₂₋₇ alkoxycarbonyl group, a 5 to 7-membered cycloalkyl group, a phenyl or naphthyl group; a C₂₋₆ hydroxyalkyl group; an aliphatic acyloxyalkyl group having a C₂₋₇ acyl group and a C₁₋₆ alkyl group; a C₁₋₆ alkyl group substituted with a C₁₋₆ alkoxy group, a carboxyl group, a C₂₋₇ alkoxycarbonyl group, a C₂₋₇ alkoxycarbonyl group substituted with a phenyl or naphthyl group, a carbamoyl group, a mono- or di-(C₁₋₆ alkyl)-substituted carbamoyl group or a cyano group; a benzoyl or naphthoyl group optionally substituted with one or more halogen atoms; a furoyl group or a pyridylcarbonyl group; and R¹ represents a C₁₋₆ alkyl group optionally substituted with one or more halogen atoms, a phenyl or a naphthyl group; the carbon atom marked “*” represents a carbon atom in (R)-configuration, (S)-configuration or a mixture thereof.
 26. The method according to claim 25, characterized in that said compound of formula (I) essentially is a form selected from the group consisting of its R-isomeric form, its S-isomeric form and its racemic form.
 26. The method according to claim 25, wherein the compound of formula (I) is KMD
 3213. 27. The method according to claim 25, wherein said compound of formula (I) is administered through mammalian skin in a steady state flux rate of at least 0.5 mg/day.
 28. The method according to claim 25, wherein the compound of formula (I) is administered using the device for transdermal administration according to claim
 1. 29. The method according to claim 25, wherein the compound of formula (I) is administered in form of an ointment, cream, spray, gel or film.
 30. The method according to claim 25, wherein the urinary tract disorder is benign prostatic hypertrophy. 